Anthrax disease progresses from initial infection to serious systemic illness due to the ability of Bacillus anthracis to avoid clearance by the host immune system. Anthrax toxin, composed of protective antigen (PA), edema factor (EF), and lethal factor (LF), is a major contributing factor to disease as the toxin suppresses immune cell function. Thus, insights into the mechanism of action for anthrax toxin provides critical information necessary for understanding the pathogenesis of B. anthracis. In the current project experiments are designed to elucidate the effects of edema toxin (ET: PA plus EF) on innate immune responses, and determine how ET combines with lethal toxin (LT: PA plus LF) to accomplish this process. After translocation into the cell by PA, EF functions as an adenylate cyclase and generates high levels of cAMP. In recent studies we have discovered that ET activates glycogen synthase kinase-3|3 (GSK- 3(3) leading to inactivation p-catenin and loss in (3-catenin cotranscriptional regulation. The goal of these studies are now to elucidate the impact ET-mediated disruption immune cell function and the effects of this process on human alveolar macrophages and peripheral blood mononuclear cells, as well as determine the combined effects of ET and LT on these cells. The specific aims of this project are: Specific Aim 1: We will characterize the ET-induced changes in inflammatory responses and intracellular signaling that account for critical immunosuppression during early stages of inhalational anthrax Specific Aim 2: We will characterize the ET-induced changes in inflammatory responses and intracel signaling that account for critical immunosuppression during late stages of inhalational anthrax Specific Aim 3: We will characterize the combined effects of ET and LT on immunosuppression during both early and late stages of anthrax disease.